title: Specific inhibition of one DNMT1-including complex influences tumor initiation and progression.
abstract: BACKGROUND
  Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. To develop more specific DNMT inhibitors for efficient cancer therapy, we compared the effects of peptides designed to specifically disrupt the interaction of DNMT1 with different proteins.
  
  
  RESULTS
  Our data indicated that the use of an unspecific DNMT inhibitor (5aza-2deoxycytidine), a DNMT1 inhibitor (procainamide) or peptides disrupting the DNMT1/PCNA, DNMT1/EZH2, DNMT1/HDAC1, DNMT1/DNMT3b and DNMT1/HP1 interactions promoted or enhanced in vivo tumorigenesis in a mouse glioma model. In contrast, a peptide disrupting the DNMT1/DMAP1 interaction, which per se did not affect tumor growth, sensitized cancer cells to chemotherapy/irradiation-induced cell death. Finally, our data indicated that the peptide disrupting the DNMT1/DMAP1 interaction increased the efficiency of temozolomide treatment.
  
  
  CONCLUSIONS
  Our data suggest that the DNMT1/DMAP1 interaction could be an effective anti-cancer target and opens a new avenue for the development of new strategies to design DNMT inhibitors.
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer, 8 quai moncousu, BP7021, Nantes, 44007, France. pierre-francois.cartron@univ-nantes.fr.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Cheray
authors.forename: Romain
authors.initials: R
authors.lastname: Pacaud
authors.forename: Arulraj
authors.initials: A
authors.lastname: Nadaradjane
authors.forename: François M
authors.initials: FM
authors.lastname: Vallette
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Cartron